Abstract Recent re-evaluation of the results of the Women's Health Initiative shows that estrogen replacement within 10 years of the menopause reduced the incidence of myocardial infarction by 34%. This did not occur if women were started on HRT more than 10 years after the menopause. Similarly, others and we showed that estrogen reduces the incidence of cardiac hypertrophy and rescues the heart from ischemia/reperfusion injury in cell and mouse models. Estrogen (E2) acts through ERss to reduce cardiac hypertrophy and preserve cardiac function. An important aspect is that E2/ERss block cardiac fibrosis that is prominently caused by hypertrophic factors such as Angiotensin II (Ang II). We propose that E2/ERss block Ang II or endothelin-1 (ET-1) induced transition of the cardiac fibroblast to myofibroblast and blocks TGFss activation and signaling through SMADs 2/3. This results in decreased collagen gene transcription, as well as other genes that contribute to fibrosis. This will be tested in isolated cardiac fibroblast and mouse models. As a second focus, we propose the idea that E2/ERss up-regulates class II HDAC production and prevents transport of these anti-hypertrophic HDACs to the cytoplasm (where they cannot repress hypertrophy). We hypothesize that Ang II and ET-1 stimulate Ca++/CAM kinase-induced phosphorylation of class II HDACs that results in nuclear exclusion, blocked by E2/ERss. Reciprocally, class I HDACs stimulate cardiac hypertrophy, perhaps by causing the inactivation of GSK3ss. We propose that E2/ERss inhibits class I HDAC synthesis that is augmented by Ang II or ET-1 and also blocks the inactivating phosphorylation of GSK3ss, thus inhibiting cardiac hypertrophy. Both rodent cardiomyocyte and mouse models will be used to test these aims. Finally, we propose to test a novel ERss agonist from Wyeth Pharmaceutical in a mouse model of hypertrophy, using wild type and ERss knockout female and male mice. These data may justify in the future initial translational trials in post-menopausal women, including veterans.